Insulin-dependent diabetes mellitus is an autoimmune disease characterized by specific destruction of the insulin-producing beta cells of the islets of Langerhans of the pancreas. It is thought to be a regulated disease because the initiation of insulitis and the transition form insulitis to diabetes are neither automatic nor immediate in susceptible individuals. The overall goal of the proposed project is to define the roles of co- stimulatory molecules are important regulators of diabetes progression, different receptor: ligand pairs exerting their influences on discrete events through pathogenesis. Consequently, the major strategy is to exploit three simple, highly manipulable derivatives of the BDC2.5 TCR tg model of diabetes that permit one to specifically focus on particular events: the initiation of insulitis, the transition from insulitis to diabetes or regulatory T cell control of the insulitis to diabetes conversion. Subsequent studies begin by building on existing information on the role of the DCD28/152:CD80/86 quarter of co-stimulatory molecules in diabetes progression and move on to the exciting new challenge of elucidating the role of the recently identified co-stimulatory receptor, ICOS. The specific aims are to: i) elucidate the roles of CD152 and CD28 at disease initiation; ii) establish the function of CD80 and CD86 in the unfolding of diabetes; iii) determine the role of ICOS during diabetes development. These studies should generate novel information on the role of co- stimulatory molecules in controlling immune responses, in particular autoimmune disease; this information may suggest novel strategies for therapeutic intervention importantly, even when disease is ongoing.